Currently, the abuse of prescription opioid medications is a pervasive problem in the U.S. In addition, co-abuse of opioids and alcohol represents a significant problem from the perspective of increased toxicity and decreased success in treatment. Surprisingly few studies have examined the effects of combined administration of opioids and alcohol in humans, and no clinical studies have examined the reinforcing effects of this combination. The current proposal will systematically screen medications that show promise for treating both opioid and alcohol use disorders (OUD and AUD). The guiding principle is that a medication's effects on positive subjective responses and reinforcing effects are the best laboratory procedures to date in predicting its clinical efficacy.In separate studies, we will test suvorexant (Study 1), oxytocin (Study 2), varenicline (Study 3), and gabapentin (Study 4) for their ability to alter opioid-, alcohol-, and combined opioid/alcohol-mediated responses. Participants in all of the studies will meet DSM-5 criteria for moderate-severe OUD and be physically dependent on opioids. In addition, all participants will meet DSM-5 criteria for moderate-severe AUD, but they will not be physically dependent on alcohol. All of the participants will be maintained on sublingual buprenorphine/naloxone throughout the studies and different doses of suvorexant, oxytocin, varenicline, and gabapentin will be evaluated. Overall, the proposed studies will provide a great deal of information about the safety and clinical utility of buprenorphine/naloxone in combination with each of the test medications for treating co-abuse of opioids and alcohol.